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BACKGROUND: The incidence of prostate cancer is increasing in older males globally. Age, ethnicity, and family history are identified as the well-known risk factors for prostate cancer, but few modifiable factors have been firmly established. The objective of this study was to identify and evaluate various factors modifying the risk of prostate cancer reported in meta-analyses of prospective observational studies and mendelian randomization (MR) analyses. METHODS AND FINDINGS: We searched PubMed, Embase, and Web of Science from the inception to January 10, 2022, updated on September 9, 2023, to identify meta-analyses and MR studies on prostate cancer. Eligibility criteria for meta-analyses were (1) meta-analyses including prospective observational studies or studies that declared outcome-free at baseline; (2) evaluating the factors of any category associated with prostate cancer incidence; and (3) providing effect estimates for further data synthesis. Similar criteria were applied to MR studies. Meta-analysis was repeated using the random-effects inverse-variance model with DerSimonian-Laird method. Quality assessment was then conducted for included meta-analyses using AMSTAR-2 tool and for MR studies using STROBE-MR and assumption evaluation. Subsequent evidence grading criteria for significant associations in meta-analyses contained sample size, P values and 95% confidence intervals, 95% prediction intervals, heterogeneity, and publication bias, assigning 4 evidence grades (convincing, highly suggestive, suggestive, or weak). Significant associations in MR studies were graded as robust, probable, suggestive, or insufficient considering P values and concordance of effect directions. Finally, 92 selected from 411 meta-analyses and 64 selected from 118 MR studies were included after excluding the overlapping and outdated studies which were published earlier and contained fewer participants or fewer instrument variables for the same exposure. In total, 123 observational associations (45 significant and 78 null) and 145 causal associations (55 significant and 90 null) were categorized into lifestyle; diet and nutrition; anthropometric indices; biomarkers; clinical variables, diseases, and treatments; and environmental factors. Concerning evidence grading on significant associations, there were 5 highly suggestive, 36 suggestive, and 4 weak associations in meta-analyses, and 10 robust, 24 probable, 4 suggestive, and 17 insufficient causal associations in MR studies. Twenty-six overlapping factors between meta-analyses and MR studies were identified, with consistent significant effects found for physical activity (PA) (occupational PA in meta: OR = 0.87, 95% CI: 0.80, 0.94; accelerator-measured PA in MR: OR = 0.49, 95% CI: 0.33, 0.72), height (meta: OR = 1.09, 95% CI: 1.06, 1.12; MR: OR = 1.07, 95% CI: 1.01, 1.15, for aggressive prostate cancer), and smoking (current smoking in meta: OR = 0.74, 95% CI: 0.68, 0.80; smoking initiation in MR: OR = 0.91, 95% CI: 0.86, 0.97). Methodological limitation is that the evidence grading criteria could be expanded by considering more indices. CONCLUSIONS: In this large-scale study, we summarized the associations of various factors with prostate cancer risk and provided comparisons between observational associations by meta-analysis and genetically estimated causality by MR analyses. In the absence of convincing overlapping evidence based on the existing literature, no robust associations were identified, but some effects were observed for height, physical activity, and smoking.
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Análisis de la Aleatorización Mendeliana , Neoplasias de la Próstata , Masculino , Humanos , Anciano , Factores de Riesgo , Neoplasias de la Próstata/epidemiología , Neoplasias de la Próstata/genética , Fumar/efectos adversos , Fumar Tabaco , Estudios Observacionales como AsuntoRESUMEN
Perioperative neurocognitive dysfunction (PND) emerges as a common postoperative complication among elderly patients. Currently, the mechanism of PND remains unclear, but there exists a tendency to believe that inflammation plays a significant role in PND. Alterations in the abundance of intestinal microbiota can increase the permeability of the intestinal mucosal barrier and incite extraintestinal inflammatory responses. Metabolites from these microbiota can be absorbed by the intestinal mucosa into the bloodstream, exerting influence upon the central nervous system (CNS). Lactobacillus (Lac), serving as an intestinal probiotic bacterium, possesses the capacity to modulate emotional behavior and cognitive functions. Extracellular vesicles (EVs) are recognized as novel therapeutic carriers for targeted delivery to regulate physiology and pathogenesis. While the mechanism governing the primary function of Lac-EVs in the CNS remains uncertain. Therefore, we established an in vitro neuroinflammation model to induce PND and then treated the mice with Lac-EVs to observe the effect of these EVs on neuroinflammation, particularly on microglial (MG) polarization. Our research unveils that Lac-EVs reduced inflammation induced by LPS in microglia and the activation of related proteins, including the mRNA expression of M1 labeled protein (iNOS). Moreover, the mRNA expression of M2-labeled protein (Arg1) increased. In addition, flow cytometry revealed that the ratio of M1/M2 microglia also changed significantly. Therefore, Lac-EVs promoted the differentiation of M2 microglia by inducing the preferential expression of specific markers related to M2 macrophages and inflammation. In terms of inflammatory cytokine expression, Lac-EVs decreased the secretion of proinflammatory cytokines (IL-1ß and IL-6) and increased IL-10 production after lipopolysaccharide (LPS) stimulation. Therefore, Lac-EVs induce the activation of M2 microglial cells without inducing cellular harm in vitro, and they demonstrate anti-inflammatory effects against lipopolysaccharide-induced neuroinflammation. This finding suggested that it is an effective anti-inflammatory strategy for alleviating inflammation-driven PNDs.
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Vesículas Extracelulares , Microglía , Humanos , Ratones , Animales , Anciano , Microglía/metabolismo , Lipopolisacáridos/metabolismo , Enfermedades Neuroinflamatorias , Citocinas/metabolismo , Antiinflamatorios/farmacología , Inflamación/tratamiento farmacológico , Vesículas Extracelulares/metabolismo , ARN Mensajero/metabolismoRESUMEN
BACKGROUND: Insulin resistance is linked to an increased risk of frailty, yet the comprehensive relationship between the triglyceride glucose-body mass index (TyG-BMI), which reflects weight, and frailty, remains unclear. This relationship is investigated in this study. METHODS: Data from 9135 participants in the China Health and Retirement Longitudinal Study (2011-2020) were analysed. Baseline TyG-BMI, changes in the TyG-BMI and cumulative TyG-BMI between baseline and 2015, along with the frailty index (FI) over nine years, were calculated. Participants were grouped into different categories based on TyG-BMI changes using K-means clustering. FI trajectories were assessed using a group-based trajectory model. Logistic and Cox regression models were used to analyse the associations between the TyG-BMI and FI trajectory and frail incidence. Nonlinear relationships were explored using restricted cubic splines, and a linear mixed-effects model was used to evaluate FI development speed. Weighted quantile regression was used to identify the primary contributing factors. RESULTS: Four classes of changes in the TyG-BMI and two FI trajectories were identified. Individuals in the third (OR = 1.25, 95% CI: 1.10-1.42) and fourth (OR = 1.83, 95% CI: 1.61-2.09) quartiles of baseline TyG-BMI, those with consistently second to highest (OR = 1.49, 95% CI: 1.32-1.70) and the highest (OR = 2.17, 95% CI: 1.84-2.56) TyG-BMI changes, and those in the third (OR = 1.20, 95% CI: 1.05-1.36) and fourth (OR = 1.94, 95% CI: 1.70-2.22) quartiles of the cumulative TyG-BMI had greater odds of experiencing a rapid FI trajectory. Higher frail risk was noted in those in the fourth quartile of baseline TyG-BMI (HR = 1.42, 95% CI: 1.28-1.58), with consistently second to highest (HR = 1.23, 95% CI: 1.12-1.34) and the highest TyG-BMI changes (HR = 1.58, 95% CI: 1.42-1.77), and those in the third (HR = 1.10, 95% CI: 1.00-1.21) and fourth quartile of cumulative TyG-BMI (HR = 1.46, 95% CI: 1.33-1.60). Participants with persistently second-lowest to the highest TyG-BMI changes (ß = 0.15, 0.38 and 0.76 respectively) and those experiencing the third to fourth cumulative TyG-BMI (ß = 0.25 and 0.56, respectively) demonstrated accelerated FI progression. A U-shaped association was observed between TyG-BMI levels and both rapid FI trajectory and higher frail risk, with BMI being the primary factor. CONCLUSION: A higher TyG-BMI is associated with the rapid development of FI trajectory and a greater frail risk. However, excessively low TyG-BMI levels also appear to contribute to frail development. Maintaining a healthy TyG-BMI, especially a healthy BMI, may help prevent or delay the frail onset.
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Biomarcadores , Glucemia , Índice de Masa Corporal , Anciano Frágil , Fragilidad , Evaluación Geriátrica , Triglicéridos , Humanos , Masculino , Fragilidad/epidemiología , Fragilidad/diagnóstico , Fragilidad/sangre , Femenino , Persona de Mediana Edad , Anciano , China/epidemiología , Incidencia , Glucemia/metabolismo , Triglicéridos/sangre , Factores de Riesgo , Medición de Riesgo , Estudios Longitudinales , Factores de Tiempo , Factores de Edad , Biomarcadores/sangre , Resistencia a la Insulina , Pronóstico , Anciano de 80 o más AñosRESUMEN
BACKGROUND: The protein annexin A6 (AnxA6) is involved in numerous membrane-related biological processes including cell migration and invasion by interacting with other proteins. The dysfunction of AnxA6, including protein expression abundance change and imbalance of post-translational modification, is tightly related to multiple cancers. Herein we focus on the biological function of AnxA6 SUMOylation in hepatocellular carcinoma (HCC) progression. METHODS: The modification sites of AnxA6 SUMOylation were identified by LC-MS/MS and amino acid site mutation. AnxA6 expression was assessed by immunohistochemistry and immunofluorescence. HCC cells were induced into the epithelial-mesenchymal transition (EMT)-featured cells by 100 ng/mL 12-O-tetradecanoylphorbol-13-acetate exposure. The ability of cell migration was evaluated under AnxA6 overexpression by transwell assay. The SUMO1 modified AnxA6 proteins were enriched from total cellular proteins by immunoprecipitation with anti-SUMO1 antibody, then the SUMOylated AnxA6 was detected by Western blot using anti-AnxA6 antibody. The nude mouse xenograft and orthotopic hepatoma models were established to determine HCC growth and tumorigenicity in vivo. The HCC patient's overall survival versus AnxA6 expression level was evaluated by the Kaplan-Meier method. RESULTS: Lys579 is a major SUMO1 modification site of AnxA6 in HCC cells, and SUMOylation protects AnxA6 from degradation via the ubiquitin-proteasome pathway. Compared to the wild-type AnxA6, its SUMO site mutant AnxA6K579R leads to disassociation of the binding of AnxA6 with RHOU, subsequently RHOU-mediated p-AKT1ser473 is upregulated to facilitate cell migration and EMT progression in HCC. Moreover, the SENP1 deSUMOylates AnxA6, and AnxA6 expression is negatively correlated with SENP1 protein expression level in HCC tissues, and a high gene expression ratio of ANXA6/SENP1 indicates a poor overall survival of patients. CONCLUSIONS: AnxA6 deSUMOylation contributes to HCC progression and EMT phenotype, and the combination of AnxA6 and SENP1 is a better tumor biomarker for diagnosis of HCC grade malignancy and prognosis.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Animales , Humanos , Ratones , Anexina A6/genética , Anexina A6/metabolismo , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular , Cromatografía Liquida , Transición Epitelial-Mesenquimal/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas de Unión al GTP rho/metabolismo , Sumoilación , Espectrometría de Masas en TándemRESUMEN
OBJECTIVE: FAT3 and LRP1B are two tumor suppressor genes with high mutation frequency in multiple cancer types, we sought to investigate the prognostic and immunological significance of these two genes in EC. METHODS: Based on a cohort of 502 EC samples, we conducted a comprehensive analysis of its multidimensional data types including genomic, transcriptomic, and clinical information, the potential impact of FAT3 and LRP1B co-mutation on antitumor immune response and prognosis were systematically discussed. RESULTS: We observed that FAT3 and LRP1B co-mutation was not only defined a dataset with prominently increased TMB, decreased tumor aneuploidy, and specially enriched in MSI-H subtype, but also manifested increased expression of immune-related markers, especially exclusive upregulation of PD-L1 levels and higher PD-L1+/CD8A+ proportion. Further analysis focused on lymphocyte infiltration and pathway enrichment explored the immune cell composition of the microenvironment and underlying molecular mechanisms affecting tumor development. Furthermore, EC patients with FAT3 and LRP1B co-mutation possessed significantly prolonged PFS and OS, and the co-mutation status was proved to be an independent prognostic factor. And a nomogram with high predictive performance was constructed by incorporating co-mutation with clinical features. More strikingly, the prognosis of MSI-H patients in EC with co-mutation was significantly improved, and their survival reached a level consistent with the POLE subtype. CONCLUSIONS: In endometrial cancer, co-mutation of FAT3 and LRP1B not only leads to activation of the immune state, but also represents a subgroup with an improved prognosis, particularly in the MSI-H subtype.
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Neoplasias Endometriales , Mutación , Receptores de LDL , Humanos , Femenino , Neoplasias Endometriales/genética , Neoplasias Endometriales/inmunología , Neoplasias Endometriales/patología , Pronóstico , Receptores de LDL/genética , Microambiente Tumoral/inmunología , Microambiente Tumoral/genética , Persona de Mediana Edad , Linfocitos Infiltrantes de Tumor/inmunología , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/inmunologíaRESUMEN
SUMOylation is an important protein post-translational modification (PTM) process, in which the small ubiquitin-like modifier (SUMO) protein covalently binds to the target protein and regulates stability, subcellular localization, and protein-protein interaction of the target protein. Protein SUMOylation exerts crucial regulatory function in the liver, and its abnormalities are associated with various liver-related disease processes. This review focuses on the biological functions of protein SUMOylation in liver-related diseases in recent years, summarizes the molecular mechanisms of SUMOylation in the replication of hepatitis viruses and the occurrence of hepatocellular carcinoma, and discusses the significance of SUMOylation in liver-related disorders, which is essential for understanding liver biological processes and formulating therapeutic strategies.
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Hepatopatías , Sumoilación , Humanos , Hepatopatías/metabolismo , Animales , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/genética , Procesamiento Proteico-Postraduccional , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/genética , Terapia Molecular Dirigida , Proteínas Modificadoras Pequeñas Relacionadas con Ubiquitina/metabolismoRESUMEN
Rare earth elements (REEs) are a new type of material resource which have attracted significant attention in recent years. REEs have emerged as essential metals in modern-day technology due to their unique functions. The long-term, large-scale mining and utilization of rare earths has caused serious environmental pollution and constitutes a global health issue, which has raised concerns regarding the safety of human health. However, the toxicity profile of suspended particulate matter in REEs in the environment, which interacts with the human body, remains largely unknown. Studies have shown that REEs can enter the human body through a variety of pathways, leading to a variety of organ and system dysfunctions through changes in genetics, epigenetics, and signaling pathways. Through an extensive literature search and critical analysis, we provide a comprehensive overview of the available evidence, identify knowledge gaps, and make recommendations for future research directions.
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Background: Breast cancer (BC) is a leading cause of mortality among women, underscoring the urgent need for improved therapeutic predictio. Developing a precise prognostic model is crucial. The role of Endoplasmic Reticulum Stress (ERS) in cancer suggests its potential as a critical factor in BC development and progression, highlighting the importance of precise prognostic models for tailored treatment strategies. Methods: Through comprehensive analysis of ERS-related gene expression in BC, utilizing both single-cell and bulk sequencing data from varied BC subtypes, we identified eight key ERS-related genes. LASSO regression and machine learning techniques were employed to construct a prognostic model, validated across multiple datasets and compared with existing models for its predictive accuracy. Results: The developed ERS-model categorizes BC patients into distinct risk groups with significant differences in clinical prognosis, confirmed by robust ROC, DCA, and KM analyses. The model forecasts survival rates with high precision, revealing distinct immune infiltration patterns and treatment responsiveness between risk groups. Notably, we discovered six druggable targets and validated Methotrexate and Gemcitabine as effective agents for high-risk BC treatment, based on their sensitivity profiles and potential for addressing the lack of active targets in BC. Conclusion: Our study advances BC research by establishing a significant link between ERS and BC prognosis at both the molecular and cellular levels. By stratifying patients into risk-defined groups, we unveil disparities in immune cell infiltration and drug response, guiding personalized treatment. The identification of potential drug targets and therapeutic agents opens new avenues for targeted interventions, promising to enhance outcomes for high-risk BC patients and paving the way for personalized cancer therapy.
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Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Pronóstico , Gemcitabina , Metotrexato , Estrés del Retículo EndoplásmicoRESUMEN
Sugarcane smut, caused by the fungal pathogen Sporisorium scitamineum, is a prominent threat to the sugarcane industry. The development of smut resistant varieties is the ultimate solution for controlling this disease, due to the lack of other efficient control methods. Artificial inoculation method is used to evaluate the virulence differentiation of pathogens. The mostly used artificial inoculation methods are soaking of the seed canes in the teliospore solution and injection of teliospores or haploid sporidia into the sugarcane sprouts. However, due to the infection nature of the pathogen that invades the sugarcane plant through meristem tissue of the sprout or shoot, the rate of successful infection is often low and fluctuated, resulting in low confidence of the assays. We recently reported a rapid and high-throughput inoculation method called plantlet soaking by using tissue culture-derived sugarcane plantlets as the test plants. Here, we compare different inoculation methods and report the characterization of parameters that may affect the sensitivity and efficiency of the plantlet soaking technique. The results showed that sugarcane plantlets were highly vulnerable to infection, even with the inoculum density at 6.0 × 105 basidial spores/ml, and this method could be applied to all varieties tested. Notably, varieties showing high smut resistance in the field exhibited high susceptibility when inoculated with the plantlet soaking method, suggesting that the plantlet soaking method is a good complement to the traditional methods for screening germplasms with internal resistance. In addition, this method could also be used to monitor the variation of cellular virulence of the smut pathogen strains in the field.
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BACKGROUND: Cinnamomum cassia Presl, a traditional Chinese medicine recorded in "Shennong's Herbal Classic," has been historically used to treat respiratory diseases and is employed to address inflammation. The essential oil derived from Cinnamomum cassia bark is a primary anti-inflammatory agent. However, there remains ambiguity regarding the chemical composition of cinnamon bark essential oil (BCEO), its principal anti-inflammatory components, and their potential efficacy in typical inflammatory respiratory conditions, such as acute lung injury (ALI). PURPOSE: This study aimed to unveil the chemical composition of BCEO. In addition, the mechanism of action of BCEO in ameliorating ALI and regulating macrophage polarization through the TLR4/MyD88/NF-κB pathway was elucidated. METHODS: BCEO was extracted using supercritical fluid extraction (SFE) and characterized through gas chromatography-mass spectrometry (GC-MS) analysis. Acute oral toxicity was observed in C57BL/6 J mice. The pharmacological effects and underlying mechanisms of BCEO were evaluated in a mouse model of ALI, which was induced by administering 5 mg/kg of lipopolysaccharide (LPS) through intratracheal instillation. RESULTS: GC-MS analysis revealed 99.08% of the constituents of BCEO. The primary components of BCEO were trans-cinnamaldehyde, o-methoxycinnamaldehyde, (+)-α-muurolene, δ-cadinene, and copaene. Oral acute toxicity tests indicated that the maximum tolerated dose of BCEO was 12 g/kg/day. BCEO treatment significantly reduced lung W/D ratio, total protein concentration in BALF, levels of TNF-α, IL-6, and IL-1ß in BALF, WBC count and NEU% in peripheral blood, and lung histological damage. Pulmonary function, IL-10 levels, and LYM% in peripheral blood also showed improvement. BCEO effectively decreased the proportion of M1 phenotype macrophages in BALF, M1/M2 ratio, and apoptotic cells in the lung tissue while increasing the proportion of M2 phenotype macrophages in BALF. Furthermore, BCEO treatment led to reduced protein and mRNA levels of TLR4, MyD88, and p-p65, alongside increased p65 expression, suggesting its potential to impede the TLR4/MyD88/NF-κB signaling pathway. CONCLUSION: SFE-extracted BCEO or its major constituents could serve as a viable treatment for ALI by reducing lung inflammation, improving pulmonary function, and protecting against LPS-induced ALI in mice. This therapeutic effect is achieved by inhibiting M1 macrophage polarization, promoting M2 macrophage polarization, and suppressing the TLR4/MyD88/NF-κB signaling pathway.
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Lesión Pulmonar Aguda , Antiinflamatorios , Cinnamomum aromaticum , Macrófagos , Aceites Volátiles , Corteza de la Planta , Animales , Masculino , Ratones , Acroleína/análogos & derivados , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/inducido químicamente , Antiinflamatorios/farmacología , Cinnamomum aromaticum/química , Modelos Animales de Enfermedad , Lipopolisacáridos , Macrófagos/efectos de los fármacos , Ratones Endogámicos C57BL , Factor 88 de Diferenciación Mieloide/metabolismo , FN-kappa B/metabolismo , Aceites Volátiles/farmacología , Aceites Volátiles/química , Corteza de la Planta/química , Transducción de Señal/efectos de los fármacos , Receptor Toll-Like 4/metabolismoRESUMEN
The delivery of chemotherapeutical drugs via nanomaterials has become a focus of pharmaceutical research over several decades due to improved drug delivery to cancer cells, decreased side effects on normal tissues, and increased therapeutic efficacy. Herein, a novel hyaluronic acid-conjugated methotrexate and 5-fluorouracil nanodrug system has been developed to address the critical limitations associated with the high toxicity and side effects of methotrexate and 5-fluorouracil. Furthermore, this nanodrug system enhances the targeting capacity of drug molecules and facilitates the potential integration of multimodal drug therapies. Concomitantly, the synergistic effects of MTX with 5-fluorouracil have been shown to improve the therapeutic index of MTX while attenuating the associated toxicities of MTX. The structure and micromorphology of the novel nanodrug can be confirmed by 1HNMR, FT-IR, UV-Vis, DLS, TEM, and AFM. Due to the ability of HA to bind to CD44 receptors activated on the surface of cancer cells and its enhanced permeability and retention (EPR) effect, the novel nanodrug we designed and synthesized can effectively target cancer cells. Cell counting Kit-8 (CCK8), flow cytometry, and live-dead staining assays in vitro showed that this nanodrug system had high targeting and antitumor activity against CD44 receptors. By using drugs to act on patient-derived colorectal, liver, and breast cancer organoids, the anticancer effect of the nanodrug was identified and verified. These results showed that the nanodrug system developed in this study may have great potential as a targeted therapy for cancer.
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Fluorouracilo , Ácido Hialurónico , Metotrexato , Metotrexato/farmacología , Metotrexato/química , Ácido Hialurónico/química , Ácido Hialurónico/farmacología , Fluorouracilo/farmacología , Fluorouracilo/química , Humanos , Sistemas de Liberación de Medicamentos , Línea Celular Tumoral , Receptores de Hialuranos/metabolismo , Portadores de Fármacos/química , Antineoplásicos/farmacología , Antineoplásicos/químicaRESUMEN
Objective: A biomechanical comparative analysis was conducted to evaluate the retrograde tibial nailing (RTN) and distal tibia plate techniques for the treatment of distal tibia fractures. Methods: Fourteen fresh adult tibia specimens were selected, consisting of seven males and seven females aged 34-55 years. The specimens were randomly divided into two groups (Group A and Group B) using a numerical table method, with seven specimens in each group. Group A underwent internal fixation of distal tibial fractures using RTN, while Group B received internal fixation using a plate. The axial compression properties of the specimens were tested in the neutral positions under pressures of 100, 200, 300, 400, and 500 N. Additionally, the torsional resistance of the two groups was assessed by subjecting the specimens to torques of 1.0, 2.0, 3.0, 4.0, and 5.0 N m. Results: At pressures of 400 and 500 N, the axial compression displacement in Group A (1.11 ± 0.06, 1.24 ± 0.05) mm was significantly smaller than that in Group B (1.21 ± 0.08, 1.37 ± 0.11) mm (p = 0.023, 0.019). Moreover, at a pressure of 500 N, the axial compression stiffness in Group A (389.24 ± 17.79) N/mm was significantly higher than that of the control group (362.37 ± 14.44) N/mm (p = 0.010). When subjected to torques of 4 and 5 N m, the torsion angle in Group A (2.97° ± 0.23°, 3.41° ± 0.17°) was significantly smaller compared to Group B (3.31° ± 0.28°, 3.76° ± 0.20°) (p = 0.035, 0.004). Furthermore, at a torque of 5 N m, the torsional stiffness in Group A (1.48 ± 0.07) N m/° was significantly higher than that in Group B (1.36 ± 0.06) N·m/° (p = 0.003). Conclusion: The results obtained from the study demonstrate that the biomechanical performance of RTN outperforms that of the distal tibial plate, providing valuable biomechanical data to support the clinical implementation of RTN.
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Calcium-based biomaterials have been intensively studied in the field of drug delivery owing to their excellent biocompatibility and biodegradability. Calcium-based materials can also deliver contrast agents, which can enhance real-time imaging and exert a Ca2+-interfering therapeutic effect. Based on these characteristics, amorphous calcium carbonate (ACC), as a brunch of calcium-based biomaterials, has the potential to become a widely used biomaterial. Highly functional ACC can be either discovered in natural organisms or obtained by chemical synthesis However, the standalone presence of ACC is unstable in vivo. Additives are required to be used as stabilizers or core-shell structures formed by permeable layers or lipids with modified molecules constructed to maintain the stability of ACC until the ACC carrier reaches its destination. ACC has high chemical instability and can produce biocompatible products when exposed to an acidic condition in vivo, such as Ca2+ with an immune-regulating ability and CO2 with an imaging-enhancing ability. Owing to these characteristics, ACC has been studied for self-sacrificing templates of carrier construction, targeted delivery of oncology drugs, immunomodulation, tumor imaging, tissue engineering, and calcium supplementation. Emphasis in this paper has been placed on the origin, structural features, and multiple applications of ACC. Meanwhile, ACC faces many challenges in clinical translation, and long-term basic research is required to overcome these challenges. We hope that this study will contribute to future innovative research on ACC.
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Obesity and related metabolic syndromes have been recognized as important disease risks, in which the role of adipokines cannot be ignored. Adiponectin (ADP) is one of the key adipokines with various beneficial effects, including improving glucose and lipid metabolism, enhancing insulin sensitivity, reducing oxidative stress and inflammation, promoting ceramides degradation, and stimulating adipose tissue vascularity. Based on those, it can serve as a positive regulator in many metabolic syndromes, such as type 2 diabetes (T2D), cardiovascular diseases, non-alcoholic fatty liver disease (NAFLD), sarcopenia, neurodegenerative diseases, and certain cancers. Therefore, a promising therapeutic approach for treating various metabolic diseases may involve elevating ADP levels or activating ADP receptors. The modulation of ADP genes, multimerization, and secretion covers the main processes of ADP generation, providing a comprehensive orientation for the development of more appropriate therapeutic strategies. In order to have a deeper understanding of ADP, this paper will provide an all-encompassing review of ADP.
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BACKGROUND: Vascular calcification refers to the abnormal accumulation of calcium in the walls of blood vessels and is a risk factor often overlooked in cardiovascular disease. However, there is currently no specific drug for treating vascular calcification. Compound Danshen Dripping Pill (CDDP) is widely used to treat cardiovascular diseases, but its effect on vascular calcification has not been reported. PURPOSE: We investigated the effects of CDDP on vascular calcification in ApoE-/- mice and in vitro and elucidated its mechanism of action. STUDY DESIGN: Firstly, we found that CDDP has the potential to improve calcification based on network pharmacology analysis. Then, we performed the following experiments: in vivo, ApoE-/- mice were fed a high-fat diet randomly supplemented with CDDP for 16 weeks. Atherosclerosis and vascular calcification were determined. In vitro, human aortic smooth muscle cells (HASMCs), human umbilical vein endothelial cells (HUVECs), and human aortic endothelial cells (HAECs) were used to determine the mechanisms for CDDP-inhibited vascular calcification. RESULTS: In this study, we observed that CDDP reduced intimal calcification in atherosclerotic lesions of ApoE-deficient mice fed a high-fat diet, as well as the calcification in cultured SMCs and ECs. Mechanistically, CDDP inhibited the Wnt/ß-catenin pathway by up-regulating the expression of DKK1 and LRP6, which are upstream inhibitors of Wnt, leading to a reduction in the expression of osteoblastic transition markers (ALP, OPN, BMP2, and RUNX2). Furthermore, CDDP enhanced the secretion of DKK1, which plays a role in mediating EC-SMC crosstalk in calcification. Additionally, VC contributes to vascular aging by inhibiting Sirt1 and increasing senescence parameters (SA-ß-gal, p21, and p16). However, CDDP reversed these changes by activating Sirt1. CDDP also reduced the levels of pro-inflammatory cytokines and the senescence-associated secretory phenotype in vivo and in vitro. CONCLUSIONS: Our study suggests that CDDP reduces vascular calcification by regulating the DKK1/LRP6/ß-catenin signaling pathway in ECs/SMCs and interactions with the crosstalk of ECs and SMCs. It also reduces the senescence of ECs/SMCs, contributing to the Sirt1 activation, indicating CDDP's novel role in ameliorating vascular calcification.
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Aterosclerosis , Dieta Alta en Grasa , Medicamentos Herbarios Chinos , Células Endoteliales de la Vena Umbilical Humana , Salvia miltiorrhiza , Calcificación Vascular , Animales , Calcificación Vascular/tratamiento farmacológico , Humanos , Medicamentos Herbarios Chinos/farmacología , Salvia miltiorrhiza/química , Masculino , Dieta Alta en Grasa/efectos adversos , Aterosclerosis/tratamiento farmacológico , Ratones , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Sirtuina 1/metabolismo , Ratones Endogámicos C57BL , Miocitos del Músculo Liso/efectos de los fármacos , Apolipoproteínas E/genética , Farmacología en Red , Vía de Señalización Wnt/efectos de los fármacos , Aorta/efectos de los fármacos , Canfanos , Péptidos y Proteínas de Señalización Intercelular , Panax notoginsengRESUMEN
Gut microbiota plays a crucial role in maintaining host homeostasis, impacting the progression and therapeutic outcomes of diseases, including inflammatory bowel disease, cancer, hepatic conditions, obesity, cardiovascular pathologies, and neurologic disorders, via immune, neural, and metabolic mechanisms. Hence, the gut microbiota is a promising target for disease therapy. The safety and precision of traditional microbiota regulation methods remain a challenge, which limits their widespread clinical application. This limitation has catalyzed a shift toward the development of multifunctional delivery systems that are predicated on microbiota modulation. Guided by bioinspired strategies, an extensive variety of naturally occurring materials and mechanisms have been emulated and harnessed for the construction of platforms aimed at the monitoring and modulation of gut microbiota. This review outlines the strategies and advantages of utilizing bioinspired principles in the design of gut microbiota intervention systems based on traditional regulation methods. Representative studies on the development of bioinspired therapeutic platforms are summarized, which are based on gut microbiota modulation to confer multiple pharmacological benefits for the synergistic management of diseases. The prospective avenues and inherent challenges associated with the adoption of bioinspired strategies in the refinement of gut microbiota modulation platforms are proposed to augment the efficacy of disease treatment.
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Microbioma Gastrointestinal , Microbioma Gastrointestinal/efectos de los fármacos , Humanos , Animales , Sistemas de Liberación de MedicamentosRESUMEN
Nao-an Dropping Pill (NADP) is a Chinese patent medicine which commonly used in clinic for ischemic stroke (IS). However, the material basis and mechanism of its prevention or treatment of IS are unclear, then we carried out this study. 52 incoming blood components were resolved by UHPLC-MS/MS from rat serum, including 45 prototype components. The potential active prototype components hydroxysafflor yellow A, ginsenoside F1, quercetin, ferulic acid and caffeic acid screened by network pharmacology showed strongly binding ability with PIK3CA, AKT1, NOS3, NFE2L2 and HMOX1 by molecular docking. In vitro oxygen-glucose deprivation/reperfusion (OGD/R) experimental results showed that NADP protected HA1800 cells from OGD/R-induced apoptosis by affecting the release of LDH, production of NO, and content of SOD and MDA. Meanwhile, NADP could improve behavioral of middle cerebral artery occlusion/reperfusion (MCAO/R) rats, reduce ischemic area of cerebral cortex, decrease brain water and glutamate (Glu) content, and improve oxidative stress response. Immunohistochemical results showed that NADP significantly regulated the expression of PI3K, Akt, p-Akt, eNOS, p-eNOS, Nrf2 and HO-1 in cerebral ischemic tissues. The results suggested that NADP protects brain tissues and ameliorates oxidative stress damage to brain tissues from IS by regulating PI3K/Akt/eNOS and Nrf2/HO-1 signaling pathways.
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Medicamentos Herbarios Chinos , Accidente Cerebrovascular Isquémico , Factor 2 Relacionado con NF-E2 , Óxido Nítrico Sintasa de Tipo III , Animales , Ratas , Apoptosis/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/uso terapéutico , Hemo Oxigenasa (Desciclizante)/metabolismo , Hemo-Oxigenasa 1/metabolismo , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Accidente Cerebrovascular Isquémico/metabolismo , Accidente Cerebrovascular Isquémico/prevención & control , Simulación del Acoplamiento Molecular , Factor 2 Relacionado con NF-E2/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Óxido Nítrico Sintasa de Tipo III/efectos de los fármacos , Óxido Nítrico Sintasa de Tipo III/metabolismo , Estrés Oxidativo/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacosRESUMEN
In the study, lycopene and resveratrol nanoemulsion hydrogel beads were prepared by using agarosesodium alginate as a carrier and the semi-interpenetrating polymer network technique, characteristics and morphologies were evaluated by scanning electron microscopy, fluorescence microscopy, rheological measurement. The synergistic antioxidant effect of lycopene and resveratrol was confirmed, the best synergistic antioxidant performance is achieved when the ratio of 1:1. To increase the solubility and improve the stability, the lycopene was prepared as solid dispersion added to the nanoemulsion. The encapsulation rate of lycopene and resveratrol reached 93.60 ± 2.94 % and 89.30 ± 1.75 %, respectively, and the cumulative release showed that the addition of agarose slowed down the release rate of the compound, which improves the applicability of lycopene and resveratrol and development of carriers for the delivery of different bioactive ingredients.
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Background: The relationship between type 2 diabetes mellitus (T2DM) and gallstone disease (GSD) have been incompletely understood. We aimed to investigate their phenotypic and genetic associations and evaluate the biological mechanisms underlying these associations. Methods: We first evaluated the phenotypic association between T2DM and GSD using data from the UK Biobank (n>450,000) using a prospective observational design. We then conducted genetic analyses using summary statistics from a meta-analysis of genome-wide association studies of T2DM, with and without adjusting for body mass index (BMI) (Ncase=74,124, Ncontrol=824,006; T2DMadjBMI: Ncase=50,409, Ncontrol=523,897) and GSD (Ncase=43,639, Ncontrol=506,798). Results: A unidirectional phenotypic association was observed, where individuals with T2DM exhibited a higher GSD risk (hazard ratio (HR)=1.39, P<0.001), but not in the reverse direction (GSDâT2DM: HR=1.00, P=0.912). The positive T2DM-GSD genetic correlation (rg=0.35, P=7.71×10-23) remained even after adjusting for BMI (T2DMadjBMI: rg=0.22, P=4.48×10-10). Mendelian randomization analyses provided evidence of a unidirectional causal relationship (T2DMâGSD: odds ratio (OR)=1.08, P=4.6×10-8; GSDâT2DM: OR=1.02, P=0.48), even after adjusting for important metabolic confounders (OR=1.02, P=0.02). This association was further corroborated through a comprehensive functional analysis reflected by 23 pleiotropic single nucleotide polymorphisms, as well as multiple neural and motor-enriched tissues. Conclusion: Through comprehensive observational and genetic analyses, our study clarified the causal relationship between T2DM and GSD, but not in the reverse direction. These findings might provide new insights into prevention and treatment strategies for T2DM and GSD.
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Diabetes Mellitus Tipo 2 , Cálculos Biliares , Humanos , Índice de Masa Corporal , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/complicaciones , Cálculos Biliares/epidemiología , Cálculos Biliares/genética , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización MendelianaRESUMEN
ABSTRACT Introduction: Transverse preputial island flap urethroplasty (TPIFU) is one of the most frequently performed technique for single-stage repair in proximal hypospadias. It was reported that the subepithelial urethroplasty would obviously decrease urethrocutaneous fistula (UF) complication after proximal TIP. But in the process of TPIFU, it had not been reported yet. Objective: We reviewed our experience to evaluate and compare the effect of continuous eversion suture (CES) versus continuous inversion subepithelial suture (CIS) on complication rates in the TPIFU. Material and methods: A retrospective review of all patients operated with CES and CIS in our institution between January 2017 and Jun 2017 was performed. Results: A total of 161 patients were enrolled in the research. Patients were followed up for 12~17 months. Total success rate was 73.9% (119/161). No statistically difference was found between the two groups with regard to age of patients (P=0.097), catheter size (P=0.52), time of catheterization (P=0.47), length of neourethra (P=0.20), non-urethral comorbidity (P=0.44) and post-operative infection (P=1.0). The overall postoperative complications had no statistically difference between the two groups (P=0.067). There were no statistically significant differences in the incidence of urethra-cutaneous fistula (UF) (OR=0.07, 95% CI: -0.24~0.037, P=0.22), urethral diverticulum (UD) (OR=0.026, 95% CI: -0.16~-0.056, P=0.323), urethral stricture (US) (OR=0.081, 95% CI: -0.15~0.15, P=1.0) and breakdown of urethral repair (BU) (OR=0.02, 95% CI: -0.118~-0.044, P=1.0). Discussion: The comparison of two group's postoperative complications was feasible because there were no statistically differences among perioperative variables. It seemed as if continuous inversion subepithelial suture would promote healing. However, it indicated that the overall success rate and the incidences of UF, UD, US and BU complications had no statistically difference between groups. It might be accounted for the subtle differences of techniques changing the process of establishing prime and side branches vascularization. Conclusions: The CIS technique had no significantly different effect on the four complications rates when compared with CES in TPIFU. Thus, CES and CIS could be randomly adopted in TPIFU as personal preference.